Therapeutic polyanhydride compounds for drug delivery

ABSTRACT

Polyanhydrides which link low molecular weight drugs containing a carboxylic acid group and an amine, thiol, alcohol, or phenol group within their structure into polymeric drug delivery systems are provided. Also provided are methods of producing polymeric drug delivery systems via these polyanhydride linkers as well as methods of administering low molecular weight drug to a host via the polymeric drug delivery systems. Medical implants based on the polymeric drug delivery system of the invention are also provided.

BACKGROUND OF THE INVENTION

Polymers comprising aromatic or aliphatic anhydrides have been studiedextensively over the years for a variety of uses. For example, in the1930s fibers comprising aliphatic polyanhydrides were prepared for usein the textile industry. In the mid 1950s, aromatic polyanhydrides wereprepared with improved film and fiber forming properties. More recently,attempts have been made to synthesize polyanhydrides with greaterthermal and hydrolytic stability and sustained drug release properties.

U.S. Pat. Nos. 4,757,128 and 4,997,904 disclose the preparation ofpolyanhydrides with improved sustained drug release properties frompure, isolated prepolymers of diacids and acetic acid. However, thesebiocompatible and biodegradable aromatic polyanhydrides have radical oraliphatic bonds resulting in compounds with slow degradation times aswell as relatively insoluble degradation products unless incorporatedinto a copolymer containing a more hydrophilic monomer, such as sebacicacid. The aromatic polyanhydrides disclosed in the '128 patent and the'904 patent are also insoluble in most organic solvents. A bioerodiblecontrolled release device produced as a homogenous polymeric matrix frompolyanhydrides with aliphatic bonds having weight average molecularweights greater than 20,000 and an intrinsic velocity greater than 0.3dL/g and a biologically active substance is also described in U.S. Pat.No. 4,888,176. Another bioerodible matrix material for controlleddelivery of bioactive compounds comprising polyanhydride polymers with auniform distribution of aliphatic and aromatic residues is disclosed inU.S. Pat. No. 4,857,311.

Biocompatible and biodegradable aromatic polyanhydrides prepared frompara-substituted bis-aromatic dicarboxylic acids for use in woundclosure devices are disclosed in U.S. Pat. No. 5,264,540. However, thesecompounds exhibit high melt and glass transition temperatures anddecreased solubility, thus making them difficult to process. Thedisclosed polyanhydrides also comprise radical or aliphatic bonds whichcan not be hydrolyzed by water.

Polyanhydride polymeric matrices have also been described for use inorthopedic and dental applications. For example, U.S. Pat. No.4,886,870, which is herein incorporated by reference in its entirety,discloses a bioerodible article useful for prosthesis and implantationwhich comprises a biocompatible, hydrophobic polyanhydride matrix. U.S.Pat. No. 5,902,599, which is herein incorporated by reference in itsentirety, also discloses biodegradable polymer networks for use in avariety of dental and orthopedic applications which are formed bypolymerizing anhydride prepolymers.

Biocompatible and biodegradable polyanhydrides have now been developedwith improved degradation, processing and solubility properties, as wellas utilities based upon their degradation products.

SUMMARY OF THE INVENTION

The present invention provides biocompatible and biodegradablepolyanhydrides which serve as the polymeric backbone linking drugmolecules into polymeric drug delivery systems. The polyanhydridepolymers of the invention demonstrate enhanced solubility andprocessability, as well as degradation properties due to the use ofhydrolyzable bonds such as esters, amides, urethanes, carbamates andcarbonates as opposed to radical or aliphatic bonds. The polyanhydridebackbone has one or more groups that will provide a therapeuticallyactive compound upon hydrolysis. The polymers of the invention compriseone or more units of formula (I) in the backbone:—C(═O)R¹—X—R²—X—R¹—C(═O)—O—  (I)wherein each R¹ is group that will provide a therapeutically activecompound upon hydrolysis of the polymer; each X is independently anamide linkage, a thioester linkage, or an ester linkage; and R² is alinking group; provided that the therapeutically active compound is notan ortho-hydroxy aryl carboxylic acid.

The polyanhydrides of the invention are used to link low molecularweight drug molecules comprising within their molecular structure onecarboxylic acid group and at least one amine, thiol, alcohol or phenolgroup. Accordingly, polyanhydrides of formula (I) serve as the polymerbackbone of polymeric drug delivery systems comprising these lowmolecular weight drugs.

Thus, the present invention also relates to compositions, methods ofproducing compositions and methods of using compositions comprising apolyanhydride of Formula (I) and low molecular weight drug moleculescontaining within their structure one carboxylic acid group and at leastone amine, thiol, alcohol or phenol group, wherein molecules of the drugare linked to one another via the polyanhydride. These polymeric drugdelivery systems provide an effective means to deliver drugs in acontrolled fashion to any site of a host. By “host” it is meant toinclude both animals and plants.

The invention also provides a pharmaceutical composition comprising apolymer of the invention and a pharmaceutically acceptable carrier.

The invention also provides a therapeutic method for treating a diseasein an animal comprising administering to an animal in need of suchtherapy, an effective amount of a polymer of the invention.

The invention also provides a method of delivering a therapeuticallyactive compound to a host comprising administering to the host abiocompatible and biodegradable polymer of the invention, which degradesinto the biologically active compound.

The invention provides a polymer of the invention for use in medicaltherapy, as well as the use of a polymer of the invention for themanufacture of a medicament useful for the treatment of a disease in amammal, such as a human.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing a polymer of the invention.

The invention also provides a polymer or composition including abiologically active compound (active agent) or drug molecule of theinvention that can be formed into a medical implant or microparticle orapplied or coated onto a medical implant or microparticle.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1. Southern Research's continuous microencapsulation processwhereby a drug, polymer and polymer solvent dispersion is added to anmechanically agitated water/surfactant mixture to form an emulsion ofmicrodroplets which is then extracted with water to remove solvent andform hardened microcapsules or microspheres for collection bycentrifugation, filtration or the like.

FIG. 2. Illustration of several hollow needle-type carriers 12 for usein the invention.

FIG. 3. Illustration of placement of pellets, “biobullets,” or seeds 10of the invention inside the hollow cavity or chamber of a bioerodableneedle-type carrier.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following definitions are used, unless otherwise described:

The article “a” and “an” as used herein refers to one or to more thanone (i.e. at least one) of the grammatical object of the article. By wayof example, “an element” means one element or more than one element.

Halo is fluoro, chloro, bromo, or iodo.

Alkyl, alkoxy, etc. denote both straight and branched groups; butreference to an individual radical such as “propyl” embraces only thestraight chain radical, a branched chain isomer such as “isopropyl”being specifically referred to.

Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to ten ring atoms in which at least one ringis aromatic.

Heteroaryl encompasses a radical attached via a ring carbon of amonocyclic aromatic ring containing five or six ring atoms consisting ofcarbon and one to four heteroatoms each selected from the groupconsisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absentor is H, O, (C₁-C₆)alkyl, phenyl or benzyl, as well as a radical of anortho-fused bicyclic heterocycle of about eight to ten ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, trimethylene, or tetramethylene diradical thereto.

The term ester linkage means —OC(═O)— or —C(═O)O—; the term thioesterlinkage means —SC(═O)— or —C(═O)S—; and the term amide linkage means—N(R)C(═O)— or —C(═O)N(R)—, wherein each R is a suitable organicradical, such as, for example, hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl,aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl. The term urethane orcarbamate linkage means —OC(═O)N(R)— or —N(R)C(═O)O—, wherein each R isa suitable organic radical, such as, for example, hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl,heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, and the termcarbonate linkage means —OC(═O)O—.

The term “amino acid,” comprises the residues of the natural amino acids(e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu,Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as wellas unnatural amino acids (e.g. phosphoserine, phosphothreonine,phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine,phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). Theterm also comprises natural and unnatural amino acids bearing aconventional amino protecting group (e.g. acetyl or benzyloxycarbonyl),as well as natural and unnatural amino acids protected at the carboxyterminus (e.g. as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide; or asan α-methylbenzyl amide). Other suitable amino and carboxy protectinggroups are known to those skilled in the art (See for example, Greene,T. W.; Wutz, P. G. M. “Protecting Groups In Organic Synthesis” secondedition, 1991, New York, John Wiley & sons, Inc., and references citedtherein).

The term “host” includes animals and plants.

The term “peptide” describes a sequence of 2 to 35 amino acids (e.g. asdefined hereinabove) or peptidyl residues. The sequence may be linear orcyclic. For example, a cyclic peptide can be prepared or may result fromthe formation of disulfide bridges between two cysteine residues in asequence. Preferably a peptide comprises 3 to 20, or 5 to 15 aminoacids. Peptide derivatives can be prepared as disclosed in U.S. Pat.Nos. 4,612,302; 4,853,371; and 4,684,620, or as described in theExamples hereinbelow. Peptide sequences specifically recited herein arewritten with the amino terminus on the left and the carboxy terminus onthe right.

Polymers of the Invention

The biocompatible, biodegradable polyanhydrides of the invention areuseful in a variety of applications where delivery of a biologicallyactive compound is desired. Examples of such applications include, butare not limited to, medical, dental and cosmetic uses.

The polymers of the invention may be prepared in accordance with methodscommonly employed in the field of synthetic polymers to produce avariety of useful products with valuable physical and chemicalproperties. The polymers can be readily processed into pastes or solventcast to yield films, coatings, microspheres and fibers with differentgeometric shapes for design of various medical implants, and may also beprocessed by compression molding and extrusion.

Medical implant applications include the use of polyanhydrides to formshaped articles such as vascular grafts and stents, bone plates,sutures, implantable sensors, implantable drug delivery devices, stentsfor tissue regeneration, and other articles that decompose intonon-toxic components within a known time period.

Polymers of the present invention can also be incorporated into oralformulations and into products such as skin moisturizers, cleansers,pads, plasters, lotions, creams, gels, ointments, solutions, shampoos,tanning products and lipsticks for topical application.

Although the invention provides homopolymers that are prepared fromsuitably functionalized biologically active compounds, Applicant hasdiscovered that the mechanical and hydrolytic properties of polymerscomprising one or more biologically active compounds can be controlledby modifying the linking group (R²) in the polymer backbone.

Preferably, the polymers of the invention comprise backbones whereinbiologically active compounds and linker groups (R²) are bonded togetherthrough ester linkages, thioester linkages, amide linkages, or a mixturethereof. Due to the presence of the ester, thioester, and/or amidelinkages, the polymers can be hydrolyzed under physiological conditionsto provide the biologically active compounds. Thus, the polymers of theinvention can be particularly useful as a controlled release source fora biologically active compound, or as a medium for the localizeddelivery of a biologically active compound to a selected site. Forexample, the polymers of the invention can be used for the localizeddelivery of a therapeutic agent to a selected site within the body of ahuman patient (i.e. within or near a tumor), where the degradation ofthe polymer provides localized, controlled, release of the therapeuticagent.

Biodegradable, biocompatible polyanhydrides which serve as linkers forlow molecular weight drug molecules have now been developed.Compositions comprising low molecular weight drugs linked viapolyanhydrides of the present invention are useful in a variety ofapplications wherein delivery of the drugs in a controlled fashion isdesired. For purposes of the present invention, by “low molecular weightdrug” it is meant to include any compound with one carboxylic acid groupand at least one amine, thiol, alcohol or phenol group within itsstructure, wherein the compound has a demonstrated pharmacologicalactivity and a molecular weight of approximately 1000 daltons or less.

In one embodiment, polyanhydrides of the present invention are preparedby the method described in Conix, Macromol. Synth., 2, 95-99 (1996). Inthis method, dicarboxylic acids are acetylated in an excess of aceticanhydride at reflux temperatures followed by melt condensation of theresulting carboxylic acid anhydride at 180° C. for 2-3 hours. Theresulting polymers are isolated by precipitation into diethylether frommethylene chloride. The described process is essentially theconventional method for polymerizing bisaromatic dicarboxylic acidanhydrides into aromatic polyanhydrides.

Polyanhydrides of the present invention have average molecular weightsranging between about 1500 daltons up to about 100,000 daltons, up toabout 100,000 daltons, calculated by Gel Permeation Chromatography (GPC)relative to narrow molecular weight polystyrene standards. Preferredaromatic polyanhydrides have average molecular weights of about 1500daltons, up to about 50,000 daltons calculated by Gel PermeationChromatography (GPC) relative to narrow molecular weight polystyrenestandards. Preferred azo-polymers have average molecular weights ofabout 1500 daltons, up to about 35,000 daltons.

Biologically Active Compounds

It has been found that the polyanhydride compounds of the invention canserve as a polymer backbone for degradable polymeric drug deliverysystems for a multitude of low molecular weight drugs. Drugs which canbe linked into degradable copolymers via the polyanhydrides have thefollowing characteristics. The drugs have a relatively low molecularweights of approximately 1,000 daltons or less. The drug must containwithin its molecular structure one carboxylic acid group. In addition,the drug must contain at least one carboxylic acid (—COOH), amine(—NHR), thiol (—SH), alcohol (—OH) or phenol (-Ph-OH) group within itsstructure.

The term “biologically active compound” includes therapeutic agents thatprovide a therapeutically desirable effect when administered to ananimal (e.g., a mammal, such as a human). Therapeutic agents that can beincorporated into the polymers of the invention include suitablyfunctionalized analgesics, anesthetics, anti-Parkinson's agents,anti-infectives, antiacne agents, antibiotics, anticholinergics,anticoagulants, anticonvulsants, antidiabetic agents, antidyskinetics,antifibrotic agents, antifibrotics, antifungal agents, antiglaucomaagents, anti-inflammatory agents, antineoplastics, antiosteoporotics,antipagetics, antisporatics, antipyretics, antiseptics/disinfectants,antithrombotics, bone resorption inhibitors, calcium regulators,cardioprotective agents, cardiovascular agents, central nervous systemstimulants, cholinesterase inhibitors, contraceptives, deodorants,dopamine receptor agonists, erectile dysfunction agents, fertilityagents, gastrointestinal agents, gout agents, hormones, hypnotics,immunomodulators, immunosuppressives, keratolytics, migraine agents,motion sickness agents, muscle relaxants, nucleoside analogs, obesityagents, ophthalmic agents, osteoporosis agents, parasympatholytics,parasympathomimetics, prostaglandins, psychotherapeutic agents,respiratory agents, sclerosing agents, sedatives, skin and mucousmembrane agents, smoking cessation agents, sympatholytics, syntheticantibacterial agents, ultraviolet screening agents, urinary tractagents, vaginal agents, and vasodilators (see Physicians' DeskReference, 55 ed., 2001, Medical Economics Company, Inc., Montvale,N.J., pages 201-202).

In a preferred embodiment, suitable examples of low molecular weightdrugs with the required functional groups within their structure can befound in almost all classes of drugs including, but not limited to,analgesics, anesthetics, antiacne agents, antibiotics, syntheticantibacterial agents, anticholinergics, anticoagulants, antidyskinetics,antifibrotics, antifungal agents, antiglaucoma agents, anti-inflammatoryagents, antineoplastics, antiosteoporotics, antipagetics,anti-Parkinson's agents, antisporatics, antipyretics,antiseptics/disinfectants, antithrombotics, bone resorption inhibitors,calcium regulators, keratolytics, sclerosing agents and ultravioletscreening agents.

The biologically active compounds can also comprise other functionalgroups (including hydroxy groups, mercapto groups, amine groups, andcarboxylic acids, as well as others) that can be used to modify theproperties of the polymer (e.g. for branching, for cross linking, forappending other molecules (e.g. another biologically active compound) tothe polymer, for changing the solubility of the polymer, or foreffecting the biodistribution of the polymer). Lists of therapeuticagents can be found, for example, in: Physicians' Desk Reference, 55ed., 2001, Medical Economics Company, Inc., Montvale, N.J.; USPNDictionary of USAN and International Drug Names, 2000, The United StatesPharmacopeial Convention, Inc., Rockville, Md.; and The Merck Index, 12ed., 1996, Merck & Co., Inc., Whitehouse Station, N.J. One skilled inthe art can readily select therapeutic agents that possess the necessaryfunctional groups for incorporation into the polymers of the inventionfrom these lists.

Examples of anti-bacterial compounds suitable for use in the presentinvention include, but are not limited to, 4-sulfanilamidosalicylicacid, acediasulfone, amfenac, amoxicillin, ampicillin, apalcillin,apicycline, aspoxicillin, aztreonam, bambermycin(s), biapenem,carbenicillin, carumonam, cefadroxil, cefamandole, cefatrizine,cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime, cefetamet,cefixime, cefmenoxime, cefminox, cefodizime, cefonicid, cefoperazone,ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran, cefpimizole,cefpiramide, cefpirome, cefprozil, cefroxadine, ceftazidime, cefteram,ceftibuten, ceftriaxone, cefuzonam, cephalexin, cephaloglycin,cephalosporin C, cephradine, ciprofloxacin, clinafloxacin, cyclacillin,enoxacin, epicillin, flomoxef, grepafloxacin, hetacillin, imipenem,lomefloxacin, lymecycline, meropenem, moxalactam, mupirocin,nadifloxacin, norfloxacin, panipenem, pazufloxacin, penicillin N,pipemidic acid, quinacillin, ritipenem, salazosulfadimidine,sparfloxacin, succisulfone, sulfachrysoidine, sulfaloxic acid,teicoplanin, temafloxacin, temocillin, ticarcillin, tigemonam,tosufloxacin, trovafloxacin, vancomycin, and the like.

Examples of anti-fungal compounds suitable for use in the presentinvention include, but are not limited to amphotericin B, azaserine,candicidin(s), lucensomycin, natamycin, nystatin, and the like.

Examples of anti-neoplastic compounds suitable for use in the presentinvention include, but are not limited to 6-diazo-5-oxo-L-norleucine,azaserine, carzinophillin A, denopterin, edatrexate, eflornithine,melphalan, methotrexate, mycophenolic acid, podophyllinic acid2-ethylhydrazide, pteropterin, streptonigrin, Tomudex®(N-((5-(((1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)methylamino)-2-thienyl)carbonyl)-L-glutamicacid), ubenimex, and the like.

Examples of anti-thrombotic compounds for use in the present inventioninclude, but are not limited to, argatroban, iloprost, lamifiban,taprostene, tirofiban and the like.

Examples of immunosuppressive compounds suitable for use in the presentinvention include, but are not limited to bucillamine, mycophenolicacid, procodazole, romurtide, ubenimex and the like.

Examples of NSAID compounds suitable for use in the present inventioninclude, but are not limited to 3-amino-4-hydroxybutyric acid,aceclofenac, alminoprofen, bromfenac, bumadizon, carprofen, diclofenac,diflunisal, enfenamic acid, etodolac, fendosal, flufenamic acid,gentisic acid, meclofenamic acid, mefenamic acid, mesalamine, niflumicacid, olsalazine oxaceprol, S-adenosylmethionine, salicylic acid,salsalate, sulfasalazine, tolfenamic acid, and the like.

Linking Group “R²”

The nature of the linking group “R²” in a polymer of the invention isnot critical provided the polymer of the invention possesses acceptablemechanical properties and release kinetics for the selected therapeuticapplication. The linking group R² is typically a divalent organicradical having a molecular weight of from about 25 daltons to about 400daltons. More preferably, R² has a molecular weight of from about 40daltons to about 200 daltons.

The linking group R² typically has a length of from about 5 angstroms toabout 100 angstroms using standard bond lengths and angles. Morepreferably, the linking group L has a length of from about 10 angstromsto about 50 angstroms.

The linking group may be biologically inactive, or may itself possessbiological activity. The linking group can also comprise otherfunctional groups (including hydroxy groups, mercapto groups, aminegroups, carboxylic acids, as well as others) that can be used to modifythe properties of the polymer (e.g. for branching, for cross linking,for appending other molecules (e.g. another biologically activecompound) to the polymer, for changing the solubility of the polymer, orfor effecting the biodistribution of the polymer).

Specific and Preferred Values

Specific and preferred values listed herein for radicals, substituents,groups, and ranges, are for illustration only; they do not exclude otherdefined values or other values within defined ranges for the radicalsand substituents.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₃-C₆)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy; (C₁-C₆)alkanoyl can be acetyl, propanoyl or butanoyl;(C₁-C₆)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, orhexyloxycarbonyl; (C₁-C₆)alkylthio can be methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, orhexylthio; (C₂-C₆)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy,isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl,indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl,triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl,pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide),thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or itsN-oxide) or quinolyl (or its N-oxide).

A specific biologically active compound that can be incorporated intothe polymers of the invention is 3-amino-4-hydroxybutyric acid,6-diazo-5-oxo-L-norleucine, aceclofenac, acediasulfone, alminoprofen,amfenac, amoxicillin, amphotericin B, ampicillin, apalcillin,apicycline, aspoxicillin, azaserine, aztreonam, bambermycin(s),biapenem, bromfenac, bucillamine, bumadizon, candicidin(s),carbenicillin, carprofen, carumonam, carzinophillin A, cefadroxil,cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir,cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefminox,cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan,cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil,cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone, cefuzonam,cephalexin, cephaloglycin, cephalosporin C, cephradine, ciprofloxacin,clinafloxacin, cyclacillin, denopterin, diclofenac, edatrexate,eflornithine, enfenamic acid, enoxacin, epicillin, etodolac, flomoxef,flufenamic acid, grepafloxacin, hetacillin, imipenem, lomefloxacin,lucensomycin, lymecycline, meclofenamic acid, mefenamic acid, melphalan,meropenem, methotrexate, moxalactam, mupirocin, mycophenolic acid,mycophenolic acid, nadifloxacin, natamycin, niflumic acid, norfloxacin,nystatin, oxaceprol, panipenem, pazufloxacin, penicillin N, pipemidicacid, podophyllinic acid 2-ethylhydrazide, procodazole, pteropterin,quinacillin, ritipenem, romurtide, S-adenosylmethionine,salazosulfadimidine, sparfloxacin, streptonigrin, succisulfone,sulfachrysoidine, sulfaloxic acid, teicoplanin, temafloxacin,temocillin, ticarcillin, tigemonam, tolfenamic acid, Tomudex®(N-((5-(((1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)methylamino)-2-thienyl)carbonyl)-L-glutamicacid), tosufloxacin, trovafloxacin, ubenimex or vancomycin.

Another specific value for R² is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbonatoms, wherein the chain is optionally substituted on carbon with one ormore (e.g. 1, 2, 3, or 4) substituents selected from the groupconsisting of (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido,cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl,and heteroaryloxy.

Another specific value for R² is an amino acid.

Another specific value for R² is a peptide.

Another specific value for R² is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbonatoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—) or (—NR—).

A more specific value for R² is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbonatoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—) or (—NR—), and wherein the chain isoptionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4)substituents selected from the group consisting of (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.

Another more specific value for R² is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 3to 15 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of thecarbon atoms is optionally replaced by (—O—) or (—NR—).

Another more specific value for R² is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 3to 15 carbon atoms.

Another more specific value for R² is a divalent, branched orunbranched, hydrocarbon chain, having from 3 to 15 carbon atoms.

A preferred value for R² is a divalent, branched or unbranched,hydrocarbon chain, having from 6 to 10 carbon atoms.

A more preferred value for R² is a divalent hydrocarbon chain having 7,8, or 9 carbon atoms.

A most preferred value for R² is a divalent hydrocarbon chain having 8carbon atoms.

A specific polyanhydride linker of the present invention comprises thestructure of formula (I):

wherein R¹ is selected from the group consisting of alkyls, cycloalkyls,substituted alkyls, aromatics, substituted aromatics, lactams, andlactones; X is selected from the group consisting of amides, thioamides,esters and thioesters; and R² is an alkyl represented by —(CH₂)_(n)—wherein n is from 1 to 20.

A specific polyanhydride polymer of the present invention includesbiologically active compounds provided that the biologically activecompound is not an alpha-hydroxy carboxylic acid.

A specific polyanhydride polymer of the present invention includesbiologically active compounds provided that the biologically activecompound is not an ortho-hydroxy aryl carboxylic acid.

Such a polymer, wherein each R¹ is a group that will provide a differentbiologically active compound upon hydrolysis of the polymer, areparticularly useful for the administration of a combination of twotherapeutic agents to an animal.

A preferred group of polyanhydride compounds includes polymers that arecomprised of compounds containing at least one free carboxylic acidgroup, and at least one alcohol group, carboxylic acid or amine groupavailable for reactions which can self-polymerize or co-polymerize withcarboxylic acid, alcohol or amine groups or bis(acyl) chlorides.

Formulations

The polymers of the invention can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally, rectally, or parenterally, by intravenous,intramuscular, intraperitoneal, intraspinal, intracranial, topical,ocular or subcutaneous routes. For some routes of administration, thepolymer can conveniently be formulated as micronized particles.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparationspreferably contain at least 0.1% of polymer by weight. The percentage ofthe compositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 80% of the weight andpreferably 2 to about 60% of a given unit dosage form. The amount ofpolymer in such therapeutically useful compositions is such that aneffective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The polymer may also be administered intravenously, intraspinal,intracranial, or intraperitoneally by infusion or injection. Solutionsof the polymer can be prepared a suitable solvent such as an alcohol,optionally mixed with a nontoxic surfactant. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, triacetin, andmixtures thereof and in oils. Under ordinary conditions of storage anduse, these preparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile solutions or dispersions or sterile powders comprisingthe polymer containing the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the polymerin the required amount in the appropriate solvent with various of theother ingredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

For topical administration, the present polymers can be applied in pureform. However, it will generally be desirable to administer them ascompositions or formulations, in combination with a dermatologicallyacceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include, alcohols or glycols or alcohol/glycol blends, in whichthe present compounds can be dissolved or dispersed at effective levels,optionally with the aid of non-toxic surfactants. Adjuvants such asfragrances and additional antimicrobial agents can be added to optimizethe properties for a given use. The resultant liquid compositions can beapplied from absorbent pads, used to impregnate bandages and otherdressings, or sprayed onto the affected area using pump-type or aerosolsprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the polymers of the invention to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Dosages

Useful dosages of the polymers can be determined by comparing their invitro activity, and in vivo activity of the therapeutic agent in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949. Additionally, useful dosages can be determined bymeasuring the rate of hydrolysis for a given polymer under variousphysiological conditions. The amount of a polymer required for use intreatment will vary not only with the particular polymer selected butalso with the route of administration, the nature of the condition beingtreated and the age and condition of the patient and will be ultimatelyat the discretion of the attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

Combination Therapies

The polymers of the invention are also useful for administering acombination of therapeutic agents to an animal. Such a combinationtherapy can be carried out in the following ways: 1) a secondtherapeutic agent can be dispersed within the polymer matrix of apolymer of the invention, and can be released upon degradation of thepolymer; 2) a second therapeutic agent can be appended to a polymer ofthe invention (i.e. not in the backbone of the polymer) with bonds thathydrolyze to release the second therapeutic agent under physiologicalconditions; 3) the polymer of the invention can incorporate twotherapeutic agents into the polymer backbone (e.g. a polymer comprisingone or more units of formula (I)) or 4) two polymers of the invention,each with a different therapeutic agent can be administered together (orwithin a short period of time).

Thus, the invention also provides a pharmaceutical compositioncomprising a polymer of the invention and a second therapeutic agentthat is dispersed within the polymer matrix of a polymer of theinvention. The invention also provides a pharmaceutical compositioncomprising a polymer of the invention having a second therapeutic agentappended to the polymer (e.g. with bonds that will hydrolyze to releasethe second therapeutic agent under physiological conditions).

The polymers of the invention can also be administered in combinationwith other therapeutic agents that are effective to treat a givencondition to provide a combination therapy. Thus, the invention alsoprovides a method for treating a disease in a mammal comprisingadministering an effective amount of a combination of a polymer of theinvention and another therapeutic agent. The invention also provides apharmaceutical composition comprising a polymer of the invention,another therapeutic agent, and a pharmaceutically acceptable carrier.

Preparation of Polymers of the Invention

Processes for preparing polyanhydride polymers of the invention areprovided as further embodiments of the invention and are illustrated bythe following procedures in which the meanings of the generic radicalsare as given above unless otherwise qualified.

For example, a polymer of the invention can be prepared, as illustratedin Scheme I, from a biologically active compound of formula (Z₁-R¹-Z₂)and a linker precursor of formula Y₁—R²—Y₂, wherein one of Z₁, and Z₂ isa carboxylic acid group and the other groups Y₁, Y₂, Z₁, and Z₂ areindependently selected from the values in the table below.

The biologically active compound and the linker precursor can bepolymerized using well known synthetic techniques (e.g. by condensation)to provide a polymer of the invention (I) wherein each X isindependently an ester linkage, a thioester linkage, or an amidelinkage.

Depending on the reactive functional group (Z₁, and Z₂) of thebiologically active compound, a corresponding functional group (Y₁ orY₂) can be selected from the following table, to provide an esterlinkage, thioester linkage, or amide linkage in the polymer backbone.Functional Group On Biologically active Functional Group On compoundLinker Precursor Resulting Linkage in (X₁ or X₂) (Z₁ or Z₂) Polymer-COOH -OH Ester -COOH -NHR Amide -COOH -SH Thioester -OH -COOH Ester -SH-COOH Thioester -NHR -COOH Amide

As will be clear to one skilled in the art, suitable protecting groupscan be used during the reaction illustrated in Scheme I (and in thereactions illustrated in Schemes II-XV below). For example, otherfunctional groups present in the biologically active compound or thelinker precursor can be protected during polymerization, and theprotecting groups can subsequently be removed to provide the polymer ofthe invention. Suitable protecting groups and methods for theirincorporation and removal are well known in the art (see for exampleGreene, T. W.; Wutz, P. G. M. “Protecting Groups In Organic Synthesis”second edition, 1991, New York, John Wiley & sons, Inc.).

Additionally, when a carboxylic acid is reacted with a hydroxy group, amercapto group, or an amine group to provide an ester linkage, thioesterlinkage, or an amide linkage, the carboxylic acid can be activated priorto the reaction, for example, by formation of the corresponding acidchloride. Numerous methods for activating carboxylic acids, and forpreparing ester linkages, thioester linkages, and amide linkages, areknown in the art (see for example Advanced Organic Chemistry: ReactionMechanisms and Structure, 4 ed., Jerry March, John Wiley & Sons, pages419-437 and 1281).

A polyanhydride/polyester of the invention can be formed from ahydroxy/carboxylic acid containing compound of formula (HOOC—R¹—OH) andfrom a linker precursor of formula HOOC—R²—COOH as illustrated in Scheme2.

A polyanhydride/polyamide of the invention can be prepared using aprocedure similar to that illustrated in Scheme 2 by replacing thebiologically active hydroxy/carboxylic acid compound in Scheme 2 with asuitable biologically active amine/carboxylic acid compound.

A polyanhydride/polythioester of the invention can be prepared using aprocedure similar to that illustrated in Scheme 2 by replacing thebiologically active hydroxy/carboxylic acid compound in Scheme 2 with asuitable mercapto/carboxylic acid compound.

Alternatively, a polyanhydride/polyester of the invention can be formedfrom a dicarboxylic acid containing compound of formula HOOC—R¹—COOH andfrom a diol linker precursor of formula (HO—R²—OH) as illustrated inScheme 3.

A polyanhydride/polyamide of the invention can be prepared using aprocedure similar to that illustrated in Scheme 2 by replacing the diollinker compound in Scheme 3 with a suitable diamine compound.

A polyanhydride/polythioester of the invention can be prepared using aprocedure similar to that illustrated in Scheme 2 by replacing the diollinker compound in Scheme 3 with a suitable dimercapto compound.

Other polymers of the invention can be formed using the reactionsdescribed herein, using starting materials that have suitable groups toprepare the desired polymer.

Polymeric drug delivery systems of the present invention can becharacterized by proton nuclear magnetic resonance (NMR) spectroscopy,infrared (IR) spectroscopy, gel permeation chromatography (GPC), highperformance liquid chromatography (HPLC), differential scanningcalorimetry (DSC), and thermal gravimetric analysis (TGA). For infraredspectroscopy, samples are prepared by solvent casting on NaCl plates. ¹Hand ¹³C NMR spectroscopy is obtained in solutions of CDCl₃ or DMSO-d₆with solvent as the internal reference.

GPC is performed to determine molecular weight and polydispersity. Inthis method, samples are dissolved in tetrahydrofuran and eluted througha mixed bed column (PE PL gel, 5 μm mixed bed) at a flow rate of 0.5mL/minute. It is preferred that the samples (about 5 mg/mL) be dissolvedinto the tetrahydrofuran and filtered using 0.5 μm PTFE syringe filtersprior to column injection. Molecular weights are determined relative tonarrow molecular weight polystyrene standards (Polysciences, Inc.).

Thermal analysis can also be performed using a system such as thePerkin-Elmer system consisting of a TGA 7 thermal gravimetric analyzerequipped with PE AD-4 autobalance and Pyris 1 DSC analyzer. In thissystem, Pyris software is used to carry out data analysis on a DECVenturis 5100 computer. For DSC, an average sample weight of 5-10 mg isheated at 10° C./minute at a 30 psi flow of N₂. For TGA, an averagesample weight of 10 mg is heated at 20° C./minute under a 8 psi flow ofN₂. Sessile drop contact angle measurements are obtained with an NRLGoniometer (Rame-hart) using distilled water. Solutions of polymer inmethylene chloride (10% wt/volume) are spun-coated onto glass slips, at5,000 rpm for 30 seconds.

Degradation and drug release profiles of the polymer drug deliverysystems of the present invention can also be determined routinely. Forthese experiments, the polymers are processed into either films,pellets, microspheres, nanospheres or fibers (depending on theirproperties). After processing, the materials are be characterized todetermine if any physicochemical changes have occurred duringprocessing. Uniform processed, weighed, and characterized samples arethen degraded in acidic, neutral, and basic phosphate buffer (conditionschosen to simulate physiological range) in triplicate. Periodically thebuffer is removed and replaced with fresh media to simulate sinkconditions. The spent buffer is analyzed by HPLC to determine thecumulative release of the drug. At defined time periods, samples areremoved from the buffer and superficially dried (blotted). They are thenweighed to determine the water uptake. At this point, the contact angle(hydrated) is also measured to determine changes in hydrophobicityduring degradation. The samples are then thoroughly dried under vacuumand weighed to determine their mass loss. Contact angles (dry) aremeasured again to determine the hydrophobicity of the dry material, andhow it compares to that of the hydrated material. By plotting cumulativerelease of the degradation products over time, the degradation kineticscan be defined. Wet and dry polymer weights over time indicate if thematerial is bulk or surface eroding. If there is an increase in wateruptake, it can be determined that the polymer is bulk eroding, whereasif there is little or no water uptake the material is consideredsurface-eroding. By plotting the changes in dry weight versus time, themass lost by the polymer as it erodes can be determined. Thisinformation will give additional insight into how the material isdegrading. Changes in molecular weight over time are also examined tobolster the degradation results.

Polyanhydride compounds of the present invention can be isolated byknown methods commonly employed in the field of synthetic polymers andused to produce a variety of drug delivery products with valuablephysical and chemical properties. Polymeric drug delivery systemscomprising the polyanhydride compounds of the invention can be readilyprocessed into pastes or solvent cast to yield films, coatings,microspheres and fibers with different geometric shapes for design ofvarious medical implants, and may also be processed by compressionmolding and extrusion. Medical implant applications include the use ofpolyanhydrides to form shaped articles such as vascular grafts andstents, bone plates, sutures, implantable sensors, implantable drugdelivery devices, stents for tissue regeneration, and other articlesthat decompose harmlessly while delivering a selected low molecularweight drug at the site of implantation within a known time period.Drugs linked via these polyanhydrides of the present invention can alsobe incorporated into oral formulations and into products such as skinmoisturizers, cleansers, pads, plasters, lotions, creams, gels,ointments, solutions, shampoos, tanning products and lipsticks fortopical application.

The quantity of polymeric drug to be administered to a host which iseffective for the selected use can be readily determined by those ofordinary skill in the art without undue experimentation. The quantityessentially corresponds stoichiometrically to the amount of drug whichis known to produce an effective treatment for the selected use.

The present invention also relates to methods of using compositionscomprising these low molecular weight drugs linked via thepolyanhydrides in any application wherein delivery of the low molecularweight drug is desired. Route of delivery is selected in accordance withdrug being administered and the condition being treated. For example,compositions of the present invention comprising a polyanhydride ofFormula (I) linking a low molecular weight drug such as, for example,amoxicillin or cephalexin can be administered orally or topically totreat bacterial infections. Similarly, compositions of the presentinvention comprising a polyanhydride of Formula (I) linking a lowmolecular weight drug such as carbidopa or levodopa can be administeredorally to patients suffering from Parkinson's disease to alleviate thesymptoms of this disease.

In one embodiment of the present invention, the polyanhydride of Formula(I) is used to link two different low molecular weight drugs into asingle polymeric drug delivery system. For example, the polyanhydride ofFormula (I) can be used to link a drug molecule of carbidopa with a drugmolecule of levodopa so that both drugs can be delivered simultaneouslyvia a single polymeric drug delivery system.

Another embodiment of the present invention includes a method of linkinglow molecular weight drug molecules containing within their structureone carboxylic acid group and at least one amine, thiol, alcohol orphenol group into polymeric drug delivery systems comprising; (a)protecting the carboxylic acid group of the low molecular weight drugmolecules; (b) adding to the low molecular weight drug molecules achlorinated polyanhydride linker of formula (IV)

wherein n is from 1 to 20, so that drug molecules displace the chlorinegroups of the polyanhydride linker of Formula (IV) and bind to thelinker via their amine, thiol, alcohol or phenol group; and (c) exposingthe linked drug molecules to heat or vacuum so that the protectinggroups are removed. In a preferred compound of formula (IV) n is from6-8.

The linking of a drug in a anhydride polymer of the present invention isshown in the following schemes. The carboxylic acid group of the lowmolecular weight drug molecule is protected, preferably via acetylation.The protected drug molecules are then exposed to the linker of thelinker of formula (IV), optionally in an activated form, e.g., thechlorinated form and bind to the linker (R²) via the amine, thiol,alcohol or phenol groups of the drug molecules. The drug and linker arethen exposed to heat and/or vacuum to remove the protecting groups,thereby resulting in a polymeric drug delivery system. The polymers ofthe invention will have from about 10 to about 30 repeating units.

The linkage of low molecular weight drugs meeting the structuralrequirements of a single carboxylic acid group and at least one amine,thiol, alcohol or phenol group within its structure are exemplified inthe following Examples 1 and 2.

EXAMPLE 1 Synthesis of Amoxicillin Polymer

The linkage of amoxicillin in a polyanhydride of the present inventionis shown in the scheme 1. The carboxylic acid group of the low molecularweight drug molecule is protected, preferably via acetylation. Theprotected drug molecules are then exposed to a chlorinated form of thelinker of formula (IV), wherein n is 8. The amine groups from the drugmolecules displace the chlorine groups of the diacyl halide Formula (IV)and bind to the linker (R²) via the amine, groups of the drug molecules.The linked drug is exposed to heat and/or vacuum to remove theprotecting groups, thereby resulting in a polymeric drug deliverysystem.

EXAMPLE 2 Synthesis of Cephalexin Polymer

A cephalexin polymer is prepared as depicted in scheme 2. The carboxylicacid group of cephalexin is first protected, for example with a benzylicgroup. The drug is then linked to sebacoyl chloride (formula (IV) wheren is 8). Following this linkage, the protecting groups are removed toproduce carboxylic acids which are then acetylated to produce monomer.The monomer is polymerized as a melt.

EXAMPLE 3

Other polymeric drug delivery systems can be prepared in accordance withthis method via the polyanhydride linker of Formula (I) of the presentinvention include, but are certainly not limited to, a carbidopadelivery system, a levodopa delivery system and an amtenac deliverysystem. Homopolymers of the carbidopa and levodopa drug delivery systemsare depicted in Formulas (V) and (VI), respectively

While these structures depict homopolymers, copolymers of such drugs canalso be prepared routinely based upon the teachings provided herein.Further, polymeric drug delivery systems comprising the polyanhydride ofFormula (I) and other drugs meeting the structural requirements, namelyone carboxylic acid group, at least one amine, thiol, alcohol or phenolgroup, and having a molecular weight of approximately 1000 daltons orless can also be routinely prepared via the disclosed methods.

The above identified polymers, compounds and/or compositions including abiologically active agent or compound, or drug molecule of the inventioncan be formed into a medical implant (e.g., medical, dental, andsurgical implants) or applied or coated onto a medical implant. Forexample, in addition to the implants described above, implants forvascular, cardiovascular, coronary, peripheral vascular, orthopedic,dental, oro-maxillary, gastrointestinal, urogenital, ophthalmic,gynecological, pulmonary, surgical, physiological, metabolic,neurological, diagnostic and therapeutic uses, may be formed from orapplied or coated with the above identified polymers, compounds and/orcompositions. Such implants include, but are not limited to, stents,catheters, balloons, guidewires, grafts, sutures, meshes, jointprostheses, breast prostheses, fracture management devices, drug dosingdevices, pacemakers, mechanical pumps, dental implants (e.g., dental,oro-maxillary, and alveolar), defibrillators, and filters. Suitablemedical implants also include, but are not limited to:

-   -   the following Boston Scientific (Boston Scientific Corporation,        Natick, Mass.) products: Polaris™, NIR® Elite OTW Stent System,        NIR® Elite Monorail™ Stent System, Magic WALLSTENT® Stent        System, Radius® Self Expanding Stent, NIR® Biliary Stent System,        NIROYAL™ Biliary Stent System, WALLGRAFT® Endoprosthesis,        WALLSTENT® Endoprosthesis, RX Plastic Biliary Stents, UroMax        Ultra™ High Pressure Balloon Catheter, Passport™ Balloon on a        Wire Catheter, Excelsior™ 1018™ Microcatheter, Spinnaker® Elite™        Flow-Directed Microcatheter, Guider Softip™ XF Guide Catheters,        Sentry™ Balloon Catheters, Flexima™ APD™ Drainage Catheters with        Twist Loc™ Hub, Vaxcel™ Chronic Dialysis Catheter, PASV® PICC        Peripherally Inserted Central Catheters, Chilli® Cooled Ablation        Catheters, and Constellation® Catheters;    -   the following Cordis (Cordis, a Johnson & Johnson Company,        Piscataway, N.J.) products: BX Velocity™ Coronary Stents, Ninja        FX™ Balloon Catheters, Raptor™ Balloon Catheters, NC Raptor™        Balloon Catheters, Predator™ Balloon Catheters, Titan Mega™        Balloon Catheters, Checkmate™ Brachytherapy Catheters, Infiniti™        Diagnostic Catheters, Cinemayre™ Diagnostic Catheters,        SuperTorque Plus™ Diagnostic Catheters, and High Flow™        Diagnostic Catheters;    -   the following Medtronics (Medtronics, Inc., Minneapolis, Minn.)        products: Aneurx Stentgraft, S7 Coronary Stents, S670 Coronary        Stents, S660 Coronary Stents, BeStent 2 Coronary Stents, D1        Balloon Catheters, and D2 Balloon Catheters;    -   the following Avantec Vascular (Avantec Vascular, San Jose,        Calif.) products: Duraflex™ Coronary Stent System, and Apollo™        Coronary Dilatation Catheter;    -   the following B. Braun (B. Braun Medical Ltd., Sheffield,        England) products: Coroflex™ Coronary Stent, Cystofix™        Urogenital Catheters, and Urecath™ Urogenital Catheters;    -   the following Cook (Cook Group Inc., Bloomington, Ind.)        products: V-Flex Plus™ Coronary Stent, and CR II® Coronary        Stent;    -   the following Guidant (Guidant Corporation, Indianapolis, Ind.)        products: Multilink Penta™ Coronary Stents, Multilink Pixel™        Coronary Stents, Multilink Ultra™ Coronary Stents, Multilink        Tetra™ Coronary Stents, Multilink Tristar™ Coronary Stents,        Ancure™ Stentgraft, Dynalink™ Biliary Stents, Rx Herculink™        Biliary Stents, Omnilink™ Biliary Stents, Megalink™ Biliary        Stents, Rx Crosssail™ Balloon Dilatation Catheters, Rx        Pauersail™ Balloon Dilatation Catheters, OTW Opensail™ Balloon        Dilatation Catheters, OTW Highsail™ Balloon Dilatation        Catheters, Rx Esprit™ Balloon Dilatation Catheters, Rx Viatrac™        Peripheral Catheters, and OTW Viatrac™ Peripheral Catheters;    -   the following Ethicon (Ethicon, a Johnson & Johnson Company,        Piscataway, N.J.) products: Vicryl™ (resorbable braided coated),        Pronova™, and Panacryl™;    -   the following USS/DG Sutures (U.S. Surgical, a division of Tyco        Healthcare Group LP, Norwalk, Conn.) products: Decon II™        (coated, braided synthetic, absorbable), PolySorb™ (coated,        braided synthetic, absorbable), Dexon S™ (Uncoated, braided        synthetic, absorbable), Gut sutures (absorbable), Biosyn™        (synthetic monofilament, absorbable), Maxon™ (synthetic        monofilament, absorbable), Surgilon™ (braided nylon,        non-absorbable), Ti-Cron™ (coated, braided polyester,        non-absorbable), Surgidac™ (coated, braided polyester,        non-absorbable), SofSilk™ (coated, braided silk,        non-absorbable), Dermalon™ (nylon monofilament, non-absorbable),        Monosof™ (nylon monofilament, non-absorbable), Novafil™        (polybutester monofilament, non-absorbable), Vascufil™ (coated        polybutester monofilament, non-absorbable), Surgilene™        (polypropylene monofilament, non-absorbable), Surgipro™        (polypropylene monofilament, non-absorbable), Flexon™ (stainless        steel monofilament, non-absorbable), SURGALLOY™ needle, and        SURGALLOY™ OptiVis™ needle;    -   the following Surgical Dynamics (Surgical Dynamics, Inc., North        Haven, Conn.) products: S*D*Sorb™ (suture anchor, AnchorSew™        (suture anchor), S*D*Sorb E-Z Tac™ (bio-resorbable implant w/o        sutures), S*D*Sorb Meniscal Stapler™ (delivers bio-absorbable        repair implant), Ray Threaded Fusion Cage™ (spine), Aline™        (cervical plating system), SecureStrand™ (spinal reconstruction        cable), and Spiral Radius 90D™ (spinal rod system);    -   the following Zimmer (Zimmer, Warsaw, Ind.) products: VerSys™        cemented stem hip system, VerSys Heritage™ Hip cemented stem hip        system, VerSys™ LD/Fx cemented stem hip system, CPT™ Hip        cemented stem hip system, VerSys™ Cemented Revision/Calcar        cemented stem hip system, Mayo™ Hip porous stem hip system,        VerSys™ Beaded MidCoat porous stem hip system, VerSys™ Beaded        FullCoat Plus porous stem hip system, VerSys™ Fiber Metal        MidCoat porous stem hip system, and VerSys™ Fiber Metal Taper        porous stem hip system, VerSys™ LD/Fx press-fit hip system,        VerSys™ Cemented Revision/Calcar revision stem hip system, ZMR™        hip revision stem hip system, Trilogy™ Cup acetabular cup hip        system, ZCA™ cup acetabular cup hip system, Longevity™        polyethylene hip system, Calcicoat™ coating hip system, NexGen™        Implant knee system, NexGen™ Instruments knee system, NexGen™        Revision Instruments knee system, IM™ Instruments knee system,        MICRO-MILL™ 5-in-1 Instruments knee system, Multi-Reference™        4-in-1 knee system, V-STAT™ Instruments knee system,        Coonrad/Morrey™ elbow, Bigliani/Flatow™ shoulder, Cable Ready™        Cable Grip System, Collagraft™ Bone Graft Matrix, Herbert™ Bone        Screw, M/DN™ Intramedullary Fixation, Mini Magna-Fx™ Screw        Fixation, Magna-Fx™ Screw Fixation, Periarticular™ Plating        System, Versa-Fx™ Femoral Fixation system, Versa-Fix II™ Femoral        Fixation System, and Trabecular™ Metal;    -   and the following Alza technologies (ALZA Corporation, Mountain        View, Calif.) products: DUROS® Implant, OROS™ osmotic, D-TRANS™        transdermal, STEALTH™ liposomal, E-TRANS™ electrotransport,        Macroflux™, and ALZAMER depot;    -   as well as those described in: Stuart, M., “Technology        Strategies, Stent and Deliver,” Start-Up, Windhover's Review of        Emerging Medical Ventures, pp. 34-38, June 2000); van der        Giessen, Willem J., et al. “Marked Inflammatory Sequelae to        Implantation of Biodegradable and Nonbiodegradable Polymers in        Porcine Coronary Arteries,” Circulation, Vol. 94, No. 7, pp.        1690-1697 (Oct. 1, 1996); Gunn, J. et al., “Stent coatings and        local drug delivery,” European Heart Journal, 20, pp. 1693-1700        (1999);    -   European Patent Applications: 01301671, 00127666, 99302918,        95308988, 95306529, 95302858, 94115691, 99933575, 94922724,        97933150, 95308988, 91309923, 91906591, and 112119841;    -   PCT Publications: WO 00/187372, WO 00/170295, WO 00/145862, WO        00/143743, WO 00/044357, WO 00/009672, WO 99/03517, WO 99/00071,        WO 98/58680, WO 98/34669, WO 98/23244, and WO 97/49434;    -   U.S. application Ser. Nos. 061568, 346263, 346975, 325198,        797743, 815104, 538301, 430028, 306785, and 429459; and    -   U.S. Pat. Nos. 6,325,825, 6,325,790, 6,322,534, 6,315,708,        6,293,959, 6,289,568, 6,273,913, 6,270,525, 6,270,521,        6,267,783, 6,267,777, 6,264,687, 6,258,116, 6,254,612,        6,245,100, 6,241,746, 6,238,409, 6,214,036, 6,210,407,        6,210,406, 6,210,362, 6,203,507, 6,198,974, 6,190,403,        6,190,393, 6,171,277, 6,171,275, 6,165,164, 6,162,243,        6,140,127, 6,134,463, 6,126,650, 6,123,699, 6,120,476,        6,120,457, 6,102,891, 6,096,012, 6,090,104, 6,068,644,        6,066,125, 6,064,905, 6,063,111, 6,063,080, 6,039,721,        6,039,699, 6,036,670, 6,033,393, 6,033,380, 6,027,473,        6,019,778, 6,017,363, 6,001,078, 5,997,570, 5,980,553,        5,971,955, 5,968,070, 5,964,757, 5,948,489, 5,948,191,        5,944,735, 5,944,691, 5,938,682, 5,938,603, 5,928,186,        5,925,301, 5,916,158, 5,911,732, 5,908,403, 5,902,282,        5,897,536, 5,897,529, 5,897,497, 5,895,406, 5,893,885,        5,891,108, 5,891,082, 5,882,347, 5,882,335, 5,879,282, RE36,104,        5,863,285, 5,853,393, 5,853,389, 5,851,464, 5,846,246,        5,846,199, 5,843,356, 5,843,076, 5,836,952, 5,836,875,        5,833,659, 5,830,189, 5,827,278, 5,824,173, 5,823,996,        5,820,613, 5,820,594, 5,811,814, 5,810,874, 5,810,785,        5,807,391, 5,807,350, 5,807,331, 5,803,083, 5,800,399,        5,797,948, 5,797,868, 5,795,322, 5,792,415, 5,792,300,        5,785,678, 5,783,227, 5,782,817, 5,782,239, 5,779,731,        5,779,730, 5,776,140, 5,772,590, 5,769,829, 5,759,179,        5,759,172, 5,746,764, 5,741,326, 5,741,324, 5,738,667,        5,736,094, 5,736,085, 5,735,831, 5,733,400, 5,733,299,        5,728,104, 5,728,079, 5,728,068, 5,720,775, 5,716,572,        5,713,876, 5,713,851, 5,713,849, 5,711,909, 5,709,653,        5,702,410, 5,700,242, 5,693,021, 5,690,645, 5,688,249,        5,683,368, 5,681,343, 5,674,198, 5,674,197, 5,669,880,        5,662,622, 5,658,263, 5,658,262, 5,653,736, 5,645,562,        5,643,279, 5,634,902, 5,632,763, 5,632,760, 5,628,313,        5,626,604, 5,626,136, 5,624,450, 5,620,649, 5,613,979,        5,613,948, 5,611,812, 5,607,422, 5,607,406, 5,601,539,        5,599,319, 5,599,310, 5,598,844, 5,593,412, 5,591,142,        5,588,961, 5,571,073, 5,569,220, 5,569,202, 5,569,199,        5,562,632, 5,562,631, 5,549,580, 5,549,119, 5,542,938,        5,538,510, 5,538,505, 5,533,969, 5,531,690, 5,520,655,        5,514,236, 5,514,108, 5,507,731, 5,507,726, 5,505,700,        5,501,341, 5,497,785, 5,497,601, 5,490,838, 5,489,270,        5,487,729, 5,480,392, 6,325,800, 6,312,404, 6,264,624,        6,238,402, 6,174,328, 6,165,127, 6,152,910, 6,146,389,        6,136,006, 6,120,454, 6,110,192, 6,096,009, 6,083,222,        6,071,308, 6,048,356, 6,042,577, 6,033,381, 6,032,061,        6,013,055, 6,010,480, 6,007,522, 5,968,092, 5,967,984,        5,957,941, 5,957,863, 5,954,740, 5,954,693, 5,938,645,        5,931,812, 5,928,247, 5,928,208, 5,921,971, 5,921,952,        5,919,164, 5,919,145, 5,868,719, 5,865,800, 5,860,974,        5,857,998, 5,843,089, 5,842,994, 5,836,951, 5,833,688,        5,827,313, 5,827,229, 5,800,391, 5,792,105, 5,766,237,        5,766,201, 5,759,175, 5,755,722, 5,755,685, 5,746,745,        5,715,832, 5,715,825, 5,704,913, 5,702,418, 5,697,906,        5,693,086, 5,693,014, 5,685,847, 5,683,448, 5,681,274,        5,665,115, 5,656,030, 5,637,086, 5,607,394, 5,599,324,        5,599,298, 5,597,377, 5,578,018, 5,562,619, 5,545,135,        5,544,660, 5,514,112, 5,512,051, 5,501,668, 5,489,271,        6,319,287, 6,287,278, 6,221,064, 6,113,613, 5,984,903,        5,910,132, 5,800,515, 5,797,878, 5,769,786, 5,630,802,        5,492,532, 5,322,518, 5,279,563, 5,213,115, 5,156,597,        5,135,525, 5,007,902, 4,994,036, 4,981,475, 4,951,686,        4,929,243, 4,917,668, 4,871,356, 6,322,582, 6,319,445,        6,309,202, 6,293,961, 6,254,616, 6,206,677, 6,205,748,        6,178,622, 6,156,056, 6,128,816, 6,120,527, 6,105,339,        6,081,981, 6,076,659, 6,058,821, 6,045,573, 6,035,916,        6,035,751, 6,029,805, 6,024,757, 6,022,360, 6,019,768,        6,015,042, 6,001,121, 5,987,855, 5,975,876, 5,970,686,        5,956,927, 5,951,587, RE36,289, 5,924,561, 5,906,273, 5,894,921,        5,891,166, 5,887,706, 5,871,502, 5,871,490, 5,855,156,        5,853,423, 5,843,574, 5,843,087, 5,833,055, 5,814,069,        5,813,303, 5,792,181, 5,788,063, 5,788,062, 5,776,150,        5,749,898, 5,732,816, 5,728,135, 5,709,067, 5,704,469,        5,695,138, 5,692,602, 5,683,416, 5,681,351, 5,675,961,        5,669,935, 5,667,155, 5,655,652, 5,628,395, 5,623,810,        5,601,185, 5,571,469, 5,555,976, 5,545,180, 5,529,175,        5,500,991, 5,495,420, 5,491,955, 5,491,954, 5,487,216,        5,487,212, 5,486,197, 5,485,668, 5,477,609, 5,473,810,        5,409,499, 5,364,410, 5,358,624, 5,344,005, 5,341,922,        5,306,280, 5,284,240, 5,271,495, 5,254,126, 5,242,458,        5,236,083, 5,234,449, 5,230,424, 5,226,535, 5,224,948,        5,213,210, 5,199,561, 5,188,636, 5,179,818, 5,178,629,        5,171,251, 5,165,217, 5,160,339, 5,147,383, 5,102,420,        5,100,433, 5,099,994, 5,089,013, 5,089,012, 5,080,667,        5,056,658, 5,052,551, 5,007,922, 4,994,074, 4,967,902,        4,961,498, 4,896,767, 4,572,363, 4,555,016, 4,549,649,        4,533,041, 4,491,218, 4,483,437, 4,424,898, 4,412,614, D260,955,        4,253,563, 4,249,656, 4,127,133, D245,069, 3,972,418, 3,963,031,        3,951,261, 3,949,756, 3,943,933, 3,942,532, 3,939,969,        6,270,518, 6,213,940, 6,203,564, 6,191,236, 6,138,440,        6,135,385, 6,074,409, 6,053,086, 6,016,905, 6,015,427,        6,011,121, 5,988,367, 5,961,538, 5,954,748, 5,948,001,        5,948,000, 5,944,739, 5,944,724, 5,939,191, 5,925,065,        5,910,148, 5,906,624, 5,904,704, 5,904,692, 5,903,966,        5,891,247, 5,891,167, 5,889,075, 5,865,836, 5,860,517,        5,851,219, 5,814,051, 5,810,852, 5,800,447, 5,782,864,        5,755,729, 5,746,311, 5,741,278, 5,725,557, 5,722,991,        5,709,694, 5,709,692, 5,707,391, 5,701,664, 5,695,879,        5,683,418, 5,669,490, 5,667,528, 5,662,682, 5,662,663,        5,649,962, 5,645,553, 5,643,628, 5,639,506, 5,615,766,        5,608,962, 5,584,860, 5,584,857, 5,573,542, 5,569,302,        5,568,746, 5,566,822, 5,566,821, 5,562,685, 5,560,477,        5,554,171, 5,549,907, 5,540,717, 5,531,763, 5,527,323,        5,520,702, 5,520,084, 5,514,159, 5,507,798, 5,507,777,        5,503,266, 5,494,620, 5,480,411, 5,480,403, 5,462,558,        5,462,543, 5,460,263, 5,456,697, 5,456,696, 5,442,896,        5,435,438, 5,425,746, 5,425,445, 5,423,859, 5,417,036,        5,411,523, 5,405,358, 5,403,345, 5,403,331, 5,394,971,        5,391,176, 5,386,908, 5,383,905, 5,383,902, 5,383,387,        5,376,101, D353,672, 5,368,599, D353,002, 5,359,831, 5,358,511,        5,354,298, 5,353,922, 5,350,373, 5,349,044, 5,335,783,        5,335,775, 5,330,442, 5,325,975, 5,318,577, 5,318,575,        5,314,433, 5,312,437, 5,310,348, 5,306,290, 5,306,289,        5,306,288, 5,294,389, 5,282,832, 5,282,533, 5,280,674,        5,279,783, 5,275,618, 5,269,807, 5,261,886, 5,261,210,        5,259,846, 5,259,845, 5,249,672, 5,246,104, 5,226,912,        5,225,485, 5,217,772, 5,217,486, 5,217,485, 5,207,679, D334,860,        5,197,597, 5,192,303, D333,401, D333,400, 5,181,923, 5,178,277,        5,174,087, 5,168,619, 5,163,946, 5,156,615, 5,154,283,        5,139,514, 5,133,738, 5,133,723, 5,131,534, 5,131,131,        5,129,511, 5,123,911, 5,121,836, 5,116,358, 5,102,418,        5,099,676, 5,092,455, 5,089,011, 5,089,010, 5,087,263,        5,084,063, 5,084,058, 5,078,730, 5,067,959, 5,059,213,        5,059,212, 5,051,107, 5,046,513, 5,046,350, 5,037,429,        5,024,322, 5,019,093, 5,002,550, 4,984,941, 4,968,315,        4,946,468, 4,932,963, 4,899,743, and 4,898,156;        which are each hereby incorporated by reference in their        entirety.

In addition to those set forth above, examples of suitable classes of abiologically active agent or compound or drug molecule for inclusion inor addition to a biocompatible and biodegradable polymer or compositioninclude, but are not limited to, an antineoplastic agent oranti-metabolite agent (e.g., cladribine, camptothecin, irinotecan,topotecan, paclitaxel, methotrexate, vincristine, actinomycin-D), animmunosuppressant (e.g., rapamycin, thalidomide), an anti-thrombogenicor anticoagulant agent (e.g., fibrin, heparin binding growth factor,sodium heparin, low molecular weight heparin, hirudin, argatroban,vapiprost, D-phe-pro-arg-chloromethylketone, dipyridamole, glycoproteinIIb/IIIa inhibitors, platelet membrane receptor antibody, recombinatehirudin, thrombin inhibitor, dextran, activated protein C), ananti-inflammatory agent (e.g., salicylate (e.g., salicylic acid,aspirin, 4-aminosalicylate, 5-aminosalicylate), ketoprofen, steroids(e.g., dexamethasone, glucocorticoids, methylprednisolone, prednasone,methylprednasone, hydrocortisone), naproxyn, ibuprofen, flurbuprofin),an anti-fungal, an anti-bacterial, an anti-viral, an anti-infective oranti-biotic agent (e.g., amoxicillin, penicillin, ciprofloxacin), aprostaglandin or prostaglandin inhibitor, an angiotensin convertingenzyme inhibitor, a calcium channel blocker, oils (e.g., fish oil, omega3-fatty acid), a histamine antagonist, a HMG-CoA reductase inhibitor, amonoclonal antibody, a serotonin blocker, a phophodiesterase inhibitor,an alpha-interferon, genetically engineered epithelial cells andcombinations thereof, a quinazolinone derivative, a nucleic acidencoding an endothelial cell mitogen such as vascular endothelial growthfactor (VEGF), vitamin (e.g., alpha-tocopherol, vitamin D), a growthfactor (e.g., fibroblast growth factor antagonists, platelet derivedgrowth factors and antagonists, a bone growth factor (e.g., osteopontin,bisphosphonates (e.g., risedronate, etidonate, alendronate) and estrogenreceptor modulators (e.g., raloxifene)), an antioxidant, an endothelinreceptor antagonist, an angiopeptin, DNA and DNAzymes, a tyrosine kinaseinhibitor ST638, a polynitrosylated albumin NO donor, a natural,semi-synthetic or synthetic hormone (e.g., follicle stimulating hormone(F.S.H.) and lutenizing hormone (L.H.)), and an anti-sense to targetseffected by drugs listed above, and mixtures of one or more of the abovebiologically active agents or compounds, or drug molecules.

The term “formed into” includes within its meaning that a polymer,compound and/or composition of the invention can be physicallyconfigured into various shapes, geometries, structures andconfigurations including, but not limited to, a film, fiber, rod, coil,corkscrew, hook, cone, pellet, tablet, tube (smooth or fluted), disc,membrane, microparticle, “biobullet” (i.e., bullet shaped), seed (i.e.,bullet shaped or targeted seeds), as well as those described in theabove identified products, patents and articles, including in some casesforming medical implants that have the same, similar or completelydifferent functional characteristics compared to those functionalcharacteristics of the medical implants described in the aboveidentified products, patents and articles. The above-mentioned shapes,geometries, structures and configurations may contain additionalfeatures that will further enhance the desired application or use. Forexample, a polymer, compound and/or composition of the invention in theform of a rod, coil, or cone may have barbs that spring out uponinsertion from a needle or canula or when warmed to body temperature toreduce movement and/or expulsion.

The shape, geometry, structure or configuration of a medical implant ofthe invention will vary depending upon the use of the implant. Forexample, for treatment of a spinal cord injury or concussion to thebrain, a polymer, compound and/or composition of the invention can beformed into a medical implant in the shape of a disc for placement underthe dura or dura mater. In another example, a polymer, compound and/orcomposition of the invention can be formed into a medical implant in theshape of a membrane or tube for use in the treatment of injury or damageto the peripheral nervous system or a block of solid or foamedcomposition containing pathways drilled or otherwise formed to encouragenerve growth or bone growth. In another example, in the treatment ofcancer, a polymer, compound and/or composition of the invention can beformed into a medical implant in the shape of a pellet, microsphere,rod, membrane, disc, bullet, hook, rod or cone, with or without barbs,for insertion in a tumor excision site or for insertion within a tumor.In the above instances, bioerosion of the medical implant would yield orgenerate an active agent.

The invention also contemplates that the shape, geometry, structure orconfiguration of a medical implant of the invention can change dependingon the mode of delivery or administration and can enhance thetherapeutic effect of the medical implant. For example, a medicalimplant of the invention may be in the form of a linear rod wheninserted in needles and stored but may become coil-like or form amultiplicity of coils or corkscrew shapes as the medical implant ispushed out of the needle by a trochar. As a result of the change of theshape, geometry, structure or configuration of the medical implant,expulsion from the tumor or tumor excision site by hydraulic pressuresor body movements can be prevented and as much mass of active ingredientcan be delivered to a small region with as small a diameter needle aspossible.

The mode of delivery or administration of a medical implant of theinvention may vary depending upon the desired application and includethose known in the art as well as those set forth herein.

A polymer, compound and/or composition of the invention can be formedinto a medical implant by any means known in the art including, but notlimited to, molding (e.g., compression or blow molding) and extrusion.The medical implant may be formed from one or more of the same ordifferent polymer, compound and/or composition of the invention.

A polymer, compound and/or composition of the invention can also beapplied or coated onto a medical implant by any means known in the artincluding, but not limited to, solvent methods such as, for example,dipping and spray-drying, and non-solvent methods such as chemical vapordeposition, extrusion coating or dipping in molten polymer, compoundand/or composition of the invention. The method of preparation may varydepending on the polymer, compound and composition and/or the medicalimplant. The medical implant can be formed from or coated with one ormore layers of the same or different polymer, compound and/orcomposition of the invention.

In another example, a polymer, compound and/or composition of theinvention can be coated onto a medical implant in the shape of amembrane or tube for use in the treatment of injury or damage to theperipheral nervous system or a block of solid or foamed compositioncontaining pathways drilled or otherwise formed to encouraged nervegrowth or bone growth. In the above instances, bioerosion of the disc,membrane, tube or block would yield or generate an active agent includedwithin the polymer or composition.

The thickness of the polymer, compound and/or composition as either themedical implant itself or as applied or coated onto a medical implantwill vary depending upon one or more factors such as the physical and/orchemical characteristics of the polymer, compound and/or composition,the medical implant and/or the application or use.

For example, a coronary artery stent may be formed from or applied orcoated with a polymer, compound and/or composition of the invention to athickness of about ≦30-50 μm while a vascular stent may be applied orcoated with a polymer, compound and/or composition of the invention to athickness of about ≦100 μm and a drug delivery device may be applied orcoated with a polymer, compound and/or composition of the invention to athickness of about ≦2 mm. In another example, round films/membranes forbuccal (sublingual) administration (e.g., placement in lining of cheek,under the tongue) will have diameters of up to about 10 mm (2 cm) and athickness of about 0.5-2.0 mm.

Further the polymers, compounds and/or compositions of the invention canbe formed into micronized particles or microparticles (e.g.,microspheres and/or microcapsules). Microparticles of a polymer,compound and/or composition of the invention may be prepared by anymeans known in the art and may include one or more of the same ordifferent polymer, compound and/or composition of the invention. Forexample, the microparticles can be prepared using an oil-in-wateremulsion method whereby a polymer of the invention is dissolved in anorganic solvent. The polymer solution is then added to a stirringsolution of water and PVA (polyvinyl alcohol, which stablilizes themicroparticle) resulting in the percipitation of the desiredmicroparticles. Optionally, a homogenizer could be used. The solution isthen allowed to settle, the solvent is decanted off the solution and themicroparticles are then dried.

In another oil-in-water emulsion method, the polymer solution is addedto a solution of water and a surfactant such as PVA, which is stirredrapidly at high shear rates with, for example, a homogenizer ordispersator. After the addition of the polymer solution, the solvent isallowed to evaporate while stirring is continued. The resultingmicroparticles are recovered by decantation, filtration orcentrifugation and dried.

A microparticle of the invention can also be prepared by SouthernResearch's (Southern Research Institute, Birmingham, Ala.) continuousmicroencapsulation process as set forth in U.S. Pat. No. 5,407,609,which is incorporated herein by reference in its entirety, and isdescribed in FIG. 1, attached hereto.

According to Southern Research's continuous microencapsulation processdescribed in FIG. 1, proteins, peptides, small molecules, water-solubledrugs, hydrophobic drugs, and drugs encapsulated in lactide/glycolidepolymers can be microencapsulated to sizes of about 1-250 μm, preferably<100 μm, more preferably, <10 μm with minimal exposure to polymersolvent, high encapsulation efficiency and good yields. As shown in FIG.1, a drug, polymer and polymer solvent dispersion is added to amechanically agitated water/surfactant mixture to form an emulsion ofmicrodroplets, which is then extracted with water to remove solvent andproduce hardened microcapsules or microspheres for collection bycentrifugation, filtration or the like.

The microparticles of the invention may be formed into various shapesand geometries (e.g., spheres, and regular or irregular spheroid shapes)as well as incorporated into various formulations or compositions (e.g.,gelatin capsule, liquid formulation, spray dry formulations,formulations for use with dry powder or aerosol inhalers, compressedtablet, topical gels, topical ointments, topical powder).

As would be understood by one of skill in the art, the desired size of amicroparticle of the invention will depend on the desired applicationand mode of delivery. Modes of administration or delivery of amicroparticle of the invention include those set forth herein, includingorally, by inhalation and topically. The present invention contemplatesthe administration of a microparticle of the invention which upondegradation or bioerosion yields a smaller particle and/or active agentfor the effective treatment of a targetted organ. The present inventionalso contemplates administration of one or more of the same or differentmicroparticles of the invention having either all the same size or amixture of two or more different sizes. By varying the size of themicroparticle, the rate of bioerosion and/or the rate of generation ofactive drug and/or the location of active drug generation can becontrolled. As a result, timed (e.g., delayed and/or sustained)generation of active drug can be achieved.

For example, treatment of the inflamed wall of the colon (e.g., thetreatment of inflammatory bowel disease, infections, and the like) maybe achieved by oral administration of a microparticle of the inventioncontaining as the active agent an anti-inflammatory drug. Such amicroparticle of about 1-10 μm in size may be administered such thatupon reaching the ileum region of the small intestine, the microparticleis about 0.1-1.0 μm in size, and about 0.01-0.1 μm in size upon reachingthe colon. See for example, A. Lamprecht et al., Abstracts/Journal ofControlled Release, Vol. 72, pp. 235-237 (2001). Once in the intestine,the microparticle can be physically entrapped by the villi and/ormicrovilli of the intestinal wall and/or by the mucous lining of theintestinal wall, thereby retarding expulsion, and prolonginggastrointestinal residence time and enabling timed sustained generationof the active agent in the proximity of the intestinal wall uponbioerosion of the polymer.

Similarly, about 0.1-100 μm, preferably about 0.1-10 μm, more preferablyabout 0.1-1 μm, microparticle of the invention may be administeredorally such that blood levels of the microparticle enable perfusion ofthe active agent into the surrounding tissue upon bioerosion. In yetanother example, oral administration of a microparticle of the inventionof about ≦0.6 μm, preferably about ≦0.3 μm, more preferably about 0.1μm, may be used to deliver an active drug through the intestine andeventually to the liver via the lymph system. See for example, P. Janiet al., Pharm. Pharmacol., Vo. 42, pp. 821-826 (1990); M. Desai et al.,Pharmaceutical Research, Vol. 13, No. 12, pp. 1838-1845 (1996)

A microparticle of the invention of about ≦10 μm may be appliedtopically or ocularly.

For skin penetration, about 1-70 μm microparticle of the invention maybe used. In one preferred embodiment, about 10-70 μm microparticle ofthe invention is used for skin penetration. In another preferredembodiment, ≦10 μm microparticle of the invention is used to create aproduct that feels smooth when applied to human skin. In anotherpreferred embodiment, about 1-3 μm microparticle of the invention isused for skin penetration. However, various microparticle sizes may beused, as exemplified in PowderJect's Smart Particle™ (PowderJectPharmaceuticals, England, U.K., including those described in U.S. Pat.Nos. 6,328,714, 6,053,889 and 6,013,050) in tissue (e.g., skin, mucosa)penetration applications which appear to rely more on shape and strengthof the microparticle rather than size.

A microparticle of the invention may also be used in an inhaled delivery(e.g., direct inhalation at a certain velocity, or by aerosol spray) tothe lungs, including deep lungs, or pulmonary region. For example, amicroparticle of the invention of about 0.5-10 μm, preferably about 1-5μm, more preferably about 1-3 μm, even more preferably about 1-2 μm maybe formulated into an aerosol. For direct inhalation, about 0.5-6 μm,more preferably about 1-3 μm, microparticle may be used. See forexample, ARADIGM's (Aradigm Corporation, Hayward, Calif.) AERx® Systemas well as those described in U.S. Pat. Nos. 6,263,872, 6,131,570,6,012,450, 5,957,124, 5,934,272, 5,910,301, 5,735,263, 5,694,919,5,522,385, 5,509,404, and 5,507,277, and MicroDose's (MicroDoseTechnologies Inc., Monmouth Junction, N.J.) MicroDose DPI Inhaler aswell as those described in U.S. Pat. Nos. 6,152,130, 6,142,146,6,026,809, and 5,960,609.

A microparticle of the invention of about ≦110 μm may be used forintraarticular injections in the treatment of, for example, arthritis.

A microparticle of the invention of about 0.1-100 μm, preferably about0.1-10 μm, more preferably about 0.1-1 μm, may be admixed with asuppository (e.g., glycerin suppository).

A polymer, compound and/or composition of the invention may also beformed into pellets, “biobullets” (i.e., bullet shaped) or seeds (e.g.,bullet-shaped seeds) for inclusion in an implantable and/or injectablebioerodable, hollow carrier 12 (e.g., barrel, bullet, capsule, syringeor needle) as exemplified in FIGS. 2 and 3. Both animal and humanapplications are contemplated. FIG. 2 illustrates several hollowneedle-type carriers 12 for use in the invention. In one embodiment,hollow carriers 12 have a diameter ranging from about 0.5-10 mm.

FIG. 3 illustrates placement of pellets, “biobullets,” or seeds 10 ofthe invention inside the hollow cavity or chamber of a bioerodableneedle-type carrier. According to the invention, one or more of the sameor different pellet, “biobullet,” or seed 10 of the invention may beplaced inside the hollow carrier 12 or delivery device. The pellet,“biobullet” or seed 10 may be any size that will enable placement insidethe hollow carrier 12.

According to the invention, upon bioerosion of the pellet, “biobullet,”or seed 10, an active agent is generated.

The invention also contemplates that the hollow carrier 12 may also beformed from a polymer, compound and/or composition of the invention suchthat upon bioerosion of the hollow carrier 12, an active agent may bereleased and/or its contents (e.g., pellets, “biobullets” or seeds ofthe invention) may be released.

In one preferred embodiment, pellets, “biobullets,” or seeds 10 are madefrom a polymer of the invention containing salicylic acid admixed withfollicle stimulating hormone (F.S.H.) and/or lutenizing hormone (L.H.)which are then placed in the hollow cavity or chamber of a bioerodablehollow carrier 12 or as part of a depot formulation (e.g., LupronDepot®) for a timed release delivery of the hormones up to about 96hours in order to stimulate ovulation.

According to the invention, a pellet, “biobullet” or seed 10 of theinvention and/or one or more hollow carriers 12 containing a pellet,“biobullet,” or seed 10 of the invention may be placed in a deliverydevice (e.g., injector, gas-driven applicator). The delivery device maybe further equipped with an axially slidable sleeve (e.g., plunger),protrusions to prevent movement of the delivery device upon application(e.g., chamfered protrusions), and handgrips. Examples of suitablecarriers and/or delivery devices include, but are not limited to, thosedescribed in U.S. Pat. Nos. 6,001,385, 5,989,214, 5,549,560; WO96/13300, WO 96/09070, WO 93/23110, and EP 068053, each of which isherein incorporated by reference in its entirety.

For example, U.S. Pat. No. 5,989,214 and WO 96/13300 describe anapparatus for injecting the body of humans or animals with apharmaceutical preparation, wherein the preparation is arranged in arigid carrier, wherein the apparatus includes: a chamber into which thecarrier can be transported; and a channel connecting onto the chamberfor transporting the carrier into the body including fixation means forfixing the end of the channel relative to the skin of the body forinjecting in order to prevent a movement of the channel in the directionperpendicularly of the axis of the barrel and where according to oneembodiment the fixation means are formed by chamfered protrusions formedon the part adapted for contact with the skin of the body and extendingsubstantially in the direction of the axis of the channel. U.S. Pat. No.5,549,560, WO 93/23110, and EP 068053 describe a device for injectinghumans and animals with a pharmaceutical preparation, wherein thepreparation is held in a rigid carrier and the carrier is carriedthrough the skin into the body by means of gas pressure, and whereinduring carrying of a rigid carrier into the body by means of gaspressure the device with which the carrier is carried into the body isheld against the body. U.S. Pat. No. 5,549,560, WO 93/23110, and EP068053 also describe a device for injecting animals or humans with apharmaceutical preparation, wherein a chamber is present in which acarrier containing the pharmaceutical preparation can be placed, abarrel connecting onto this chamber and means for carrying the carrierby means of gas pressure through the barrel into the body for injecting,wherein means are present for blocking the use of the device when it isnot pressed against a body. U.S. Pat. No. 6,001,385 and WO 96/09070describe “bullets” that are at least partly manufactured fromsubstantially fully destructurized starch, particularly implants,suitable as vehicles for introducing active agents into the human oranimal body in a transdermal manner.

The range of therapeutically effective dosages, that is, the dosagelevels necessary to achieve the desired result, of a microparticle ofthe invention will be influenced by the route of administration, thetherapeutic objectives, and the condition of the patient. As such, amicroparticle of the invention may be administered as a single dailydose, several times daily, every other day, weekly, etc. depending onthe dosage requirements. Individual determinations will need to be madeto identify the optimal dosage required.

A polymer, compound and/or composition of the invention may be combinedor admixed with other ingredients prior to or while being formed into orcoated onto a medical implant or microparticle or into a particularcoating for a medical implant. Examples of suitable additives include,but are not limited to, stabilizers, mechanical stabilizers,plasticizers, hardeners, emulsifiers, other polymers including otherbiocompatible and biodegradable polymers (e.g., biocompatible andbiodegradable polyanhydrides as set forth in U.S. application Ser. No.09/917,231 and PCT Application No. US/01/23740, biocompatible andbiodegradable polyazo compounds as set forth in U.S. application Ser.No. 09/917,595 and PCT Application No. US/01/23748, biocompatible andbiodegradable polyesters, polythioesters, and polyamides as set forth inU.S. application Ser. No. 09/917,194 and PCT Application No.US/01/23747, each of which is incorporated by reference in itsentirety), radioopaque and/or radioisotopic materials (e.g., boron,iodine, etc.), suppositories, and other diagnostic or therapeutic agentsor drugs.

An added ingredient may enhance stability of the polymer, compoundand/or composition itself, the medical implant itself and/or may enhancethe diagnostic or therapeutic effect and/or may enhance or enablediagnostic activity. For example, if the added ingredient is adiagnostic or therapeutic agent or drug, bioerosion of the polymer wouldnot only generate the active agent but would also release the diagnosticor therapeutic agent. In another example, by adding a radioopaquematerial, visualization of both the targeted area (e.g., tumor site,tumor) and the medical implant (e.g., catheter) would be enabled duringand/or after (e.g., angioplasty, dental applications, joint injections,etc) insertion of the medical implant. In another example, theradioopaque material may also be used to control and/or enhancebioerosion of the medical implant and thereby control and/or enhancegeneration of the active agent by the generation of heat resulting fromneutron capture.

An added ingredient may also enhance the overall mechanical stability ofthe medical implant (e.g., carbon fibers). The type of additive usedwould vary and depend upon the desired property and application.

Activity

The ability of a polymer of the invention to produce a given therapeuticeffect can be determined using in vitro and in vivo pharmacologicalmodels which are well known to the art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. (canceled)
 2. (canceled)
 3. A method of treating arthritis comprisinginjecting into the area of the arthritis an effective amount of apolyanhydride comprising a polymer whose backbone incorporates linkagesselected from the group consisting of ester, thioester, and amidewherein the backbone also incorporates at least one group which willyield a biologically-active anti-inflammatory upon the hydrolysis of thepolymer, and further wherein the polymer comprises one or more units ofFormula I:—C(═O)R¹—X—R²—X—R¹—C(═O)—O—  (I) wherein each R¹ is a group that willprovide a therapeutically active anti-inflammatory compound uponhydrolysis of the polymer; each X is independently an amide linkage, athioester linkage, or an ester linkage; and R² is a linking group;provided that the therapeutically active compound is not anortho-hydroxy aryl carboxylic acid.